Comparison of treatment effect sizes from pivotal and postapproval trials of novel therapeutics approved by the FDA based on surrogate markers of disease: a meta-epidemiological study

Background: The U.S. Food and Drug Administration (FDA) often approves new drugs based on trials that use surrogate markers for endpoints, which involve certain trade-offs and may risk making erroneous inferences about the medical product’s actual clinical effect. This study aims to compare the treatment effects among pivotal trials supporting FDA approval of novel therapeutics based on surrogate markers of disease with those observed among postapproval trials for the same indication. Methods: We searched Drugs@FDA and PubMed to identify published randomized superiority design pivotal trials for all novel drugs initially approved by the FDA between 2005 and 2012 based on surrogate markers as primary endpoints and published postapproval trials using the same surrogate markers or patient-relevant outcomes as endpoints. Summary ratio of odds ratios (RORs) and difference between standardized mean differences (dSMDs) were used to quantify the average difference in treatment effects between pivotal and matched postapproval trials. Results: Between 2005 and 2012, the FDA approved 88 novel drugs for 90 indications based on one or multiple pivotal trials using surrogate markers of disease. Of these, 27 novel drugs for 27 indications were approved based on pivotal trials using surrogate markers as primary endpoints that could be matched to at least one postapproval trial, for a total of 43 matches. For nine (75.0%) of the 12 matches using the same non-continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than postapproval trials. On average, treatment effects were 50% higher (more beneficial) in the pivotal than the postapproval trials (ROR 1.5; 95% confidence interval CI 1.01–2.23). For 17 (54.8%) of the 31 matches using the same continuous surrogate markers as trial endpoints, pivotal trials had larger treatment effects than the postapproval trials. On average, there was no difference in treatment effects between pivotal and postapproval trials (dSMDs 0.01; 95% CI -0.15–0.16). Conclusions: Many postapproval drug trials are not directly comparable to previously published pivotal trials, particularly with respect to endpoint selection. Although treatment effects from pivotal trials supporting FDA approval of novel therapeutics based on non-continuous surrogate markers of disease are often larger than those observed among postapproval trials using surrogate markers as trial endpoints, there is no evidence of difference between pivotal and postapproval trials using continuous surrogate markers

Civil society leadership in the struggle for AIDS treatment in South Africa and Uganda

Includes abstract.Includes bibliographical references.This thesis is an attempt to theorise and operationalise empirically the notion of ‘civil society leadership’ in Sub-Saharan Africa. ‘AIDS leadership,’ which is associated with the intergovernmental institutions charged with coordinating the global response to HIV/AIDS, is both under-theorised and highly context-specific. In this study I therefore opt for an inclusive framework that draws on a range of approaches, including the literature on ‘leadership’, institutions, social movements and the ‘network’ perspective on civil society mobilisation. This framework is employed in rich and detailed empirical descriptions (‘thick description’) of civil society mobilisation around AIDS, including contentious AIDS activism, in the key case studies of South Africa and Uganda. South Africa and Uganda are widely considered key examples of poor and good leadership (from national political leaders) respectively, while the Treatment Action Campaign (TAC) and The AIDS Support Organisation (TASO) are both seen as highly effective civil society movements. These descriptions emphasise ‘transnational networks of influence’ in which civil society leaders participated (and at times actively constructed) in order to mobilise both symbolic and material resources aimed at exerting influence at the transnational, national and local levels

Achieving a fair and effective COVID-19 response: An open letter to Vice-President Mike Pence, and other federal, state and local leaders from Public Health and Legal Experts in the United States

Experts in public health, law, and human rights, with experience in previous pandemic responses, write to set forth principles and practices that should guide the efforts against COVID-19 in the US. It is essential that all institutions, public and private, address the following critical concerns through new legislation, institutional policies, leadership and spending

Reducing Sexual Violence by Increasing the Supply of Toilets in Khayelitsha, South Africa: A Mathematical Model

<div><p>Background</p><p>Sexual violence is a major public health issue, affecting 35% of women worldwide. Major risk factors for sexual assault include inadequate indoor sanitation and the need to travel to outdoor toilet facilities. We estimated how increasing the number of toilets in an urban township (Khayelitsha, South Africa) might reduce both economic costs and the incidence and social burden of sexual assault.</p><p>Methods</p><p>We developed a mathematical model that links risk of sexual assault to the number of sanitation facilities and the time a woman must spend walking to a toilet. We defined a composite societal cost function, comprising both the burden of sexual assault and the costs of installing and maintaining public chemical toilets. By expressing total social costs as a function of the number of available toilets, we were able to identify an optimal (i.e., cost-minimizing) social investment in toilet facilities.</p><p>Findings</p><p>There are currently an estimated 5600 toilets in Khayelitsha. This results in 635 sexual assaults and US$40 million in combined social costs each year. Increasing the number of toilets to 11300 would minimize total costs ($35 million) and reduce sexual assaults to 446. Higher toilet installation and maintenance costs would be more than offset by lower sexual assault costs. Probabilistic sensitivity analysis shows that the optimal number of toilets exceeds the original allocation of toilets in the township in over 80% of the 5000 iterations of the model.</p><p>Interpretation</p><p>Improving access to sanitation facilities in urban settlements will simultaneously reduce the incidence of sexual assaults and overall cost to society. Since our analysis ignores the many additional health benefits of improving sanitation in resource-constrained urban areas (e.g., potential reductions in waterborne infectious diseases), the optimal number of toilets identified here should be interpreted as conservative.</p></div

Base case and optimal scenario results summary.

<p>Base case and optimal scenario results summary.</p

Parameter values in deterministic and probabilistic sensitivity analysis (SA).

<p>Parameter values in deterministic and probabilistic sensitivity analysis (SA).</p

Toilet installation and maintenance costs and social cost of sexual assault (base case).

<p>Toilet installation and maintenance costs and social cost of sexual assault (base case).</p

Deterministic sensitivity analysis (DSA).

<p>Deterministic sensitivity analysis (DSA).</p

Probabilistic sensitivity analysis (PSA).

<p>Probabilistic sensitivity analysis (PSA).</p